Carcinogenesis, Vol. 21, No. 12, 2193-2201,
December 2000
© 2000 Oxford University Press
CANCER BIOLOGY |
Distinct mechanisms of loss of estrogen receptor 
gene expression in human breast cancer: methylation of the gene and alteration of trans-acting factors
1 Hormone-Associated Cancer Research Group, Laboratory of Cancer Diagnosis and Therapy, Saitama Cancer Center Research Institute and
2 Department of Breast Surgery, Saitama Cancer Center Hospital, 818 Komuro, Ina, Saitama 362-0806, Japan,
3 Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, S-171 77, Stockholm, Sweden and
4 Department of Critical Care Medicine and
5 Department of Second Surgery, Gunma University School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan
We have previously shown that the distal promoter (promoter B) of the estrogen receptor 
(ER) gene is responsible for the enhanced expression of the ER gene seen in human breast cancer and that a novel trans-acting factor, estrogen receptor promoter B associated factor 1 (ERBF-1), is required for transcription from promoter B in breast cancer cells. In development of breast cancer, loss of ER gene expression is one of the most important steps in acquiring hormone resistance, though the mechanisms are poorly understood. Recent studies have reported that methylation of the ER gene promoter A and exon 1 was inversely associated with ER gene expression in human breast cancer and cell lines. The methylation status of the promoter B region, which is responsible for overexpression of ER protein in cancer tissue, has not been investigated. In this report, we found that the methylation status of promoter B, as well as that of promoter A, was inversely associated with ER gene expression in human breast cancer and cell lines. Specific methylation of ER gene promoters in vitro directly decreased transcription of the ER gene in a reporter assay. Demethylating treatment induced transcription of ER mRNA from promoter B in ZR-75-1 cells, which showed no transcription from promoter B, despite weak ERBF-1 expression, but not in ER-negative MDA-MB-231 and BT-20 cells, which lack ERBF-1. ZR-75-1 cells showed promoter activity equal to that of MCF-7 cells in a reporter assay. Our results indicate that methylation of promoter B of the ER gene is important for loss of ER gene expression in human breast cancer, and methylation of the promoters can directly modulate ER gene expression. However, loss of critical transcriptional factors such as ERBF-1 may also be involved in some ER-negative cases.
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